Rats and rabbits treated chronically with adriamycin will be used as model systems for studying biochemical mechanisms underlying the development of adriamycin-induced heart muscle disease. The hypothesis that chronic adriamycin treatment may cause the degeneration of heart muscle as a consequence of stimulation of free radical reactions and lipid peroxidation which lead to disruption of the structure and function of cardiac subcellular membranes will be tested. Biochemical evidence for the occurrence of lipid peroxidation in vivo will be sought by measuring products of lipid peroxidation reactions in cardiac subcellular fractions. The methods will include measurements of degradation products of lipid peroxides by thiobarbituric acid reactivity, molecular damage end products of lipid peroxidation by specific fluorescence of lipid extracts, conjugated diene intermediates of lipid peroxidation by ultraviolet absorption spectroscopy, and quantitation of lipid hydroperoxides by iodometric titration. Biochemical measurements of lipid peroxidation will be correlated with histologic evaluations of cardiotoxicity obtained by both light and electron microscopy. The relationship between lipid peroxidation and membrane structure and function will be studied from the view that lipid peroxidation products may alter membrane architecture at a molecular level by altering lipid-lipid and lipid-protein interactions. Membrane structure will be studied by using biophysical methods, such as fluorescence and electron paramagnetic resonance spectroscopy, to monitor the behavior of extrinsic probes which partition into the hydrophobic environment of subcellular membranes. Membrane function will be investigated by measurements of membrane enzyme activities and permeability properties. These studies will include measurements of the proton conductance of the mitochondrial membrane, and energy coupling activities of heart mitochondria. Rates and mechanisms of superoxide and hydrogen peroxide generation in vitro will also be investigated. The effects of administration of antioxidants, such as Alpha-tocopherol, on lipid peroxidation and adriamycin cardiotoxicity will be explored. These studies may contribute toward an understanding of the pathogenesis of adriamycin-induced heart muscle disease.